Diphenylalkylaminomethyl pyrrolidines



Jnited States Patent DIPHENYLALKYLAMINONIETHYL PYRROLIDINES in H. Blel, Milwaukee, Wis., asslgnor to Lakeside Lablratories, Inc., Milwaukee, Wis., a corporation of Wis- 01181]! No Drawing. Application December 10, 1957 Serial No. 701,737

7 Claims. (Cl. 260-613) [his invention relates to novel chemical compounds. are particularly, this invention is concerned with cer- 1 novel derivatives of pyrrolidine.

(his application is a continuation-in-part of my colding application Serial No. 543,583, filed October 28, 5, now abandoned.

according to the present invention there are provided rel compounds of the formula 111' rr-z-wa 1 --t In N Y r v n lerein R, R, X, Y and Z have the significance previsly assigned and A is a halogen, advisably bromine or lorine. Surprisingly, the piperidine ring undergoes a 1g contraction in the reaction and yields a Z-pyrrolidyl- :thyl group. Any halopiperidines may be employed in which the logen is in the 3rd nuclear position. Examples of mpounds which may be used are N-ethyl-3-chloroperidine, N-methyl-3-bromopiperidine, and thelike. Benzhydrylamine as well as N-alkyl-benzhydrylamines 1y be used in this process and the phenyl' groups of such mpounds may also be nuclear substituted as previously iicated. In addition, related diphenylalkylamines such 2,2 diphenylethylamine, N methyl 3,3 diphenyl opylamine and 4-(p-chlorophenyl)-4-phenyl-butylamine 1y also be used. The reaction is conveniently achieved by contacting the actants in the presence of an inert organic solvent at :vated temperatures such as the reflux temperature. 'lvents such as the lower alcohols, hexane and ether ay be used. Sodamide may be added to maintain basic action conditions. At reflux temperature, reaction times ice of about 3 through 12 hours are generally adequate to complete the reaction. After the reaction is completed, the solvent may be removed under reduced pressure, leaving the product as a residual oil. It is purified by adding it to alkaline water and extraction with ether. After the ether is removed the product may be collected by fractional distillation. I

Representative of the products which may be produced by this process using reactants such as indicated above are N-methyl-2-(benzhydrylaminomethyl)-pyrrolidine, N- methyl 2 (p chlorobenzhydrylaminomethyl) pyr rolidine, N (N' methyl 2 pyrrolidylmethyl) N methyl benzhydrylamine, N ethyl 2 (3,3 diphenyl propylamino-methyl) pyrrolidine, N propyl 2 (4,4 diphenylbutylaminomethyl) pyrrolidine, N methyl 2 (p methylbenzhydrylaminomethyl) pyrrolidine, N ethyl 2 (p ethoxybenzhydrylaminomethyl) pyr rolidine, and N propyl 2 (p nitrobenzhydrylmethyl aminomethyl) pyrrolidine.

Acid addition salts of the pyrrolidines and N-alkyl pyrrolidines of this invention are produced by contacting them with a suitable acid such as a mineral acid like sulfuric acid, or hydrochloric acid or organic acids like formic acid, citric acid, fumaric acid and maleic acid. One or two equivalents of acid may be reacted per mole of compound to produce monoor di-salts thereof.

Quaternary ammonium salts are also readily prepared by contacting the compounds with alkyl and aralkyl esters of mineral and organic acids, preferably in the presence of an organic solvent. Alkyl halides such as methyl chloride, and ethyl bromide and dimethyl sulfate are representative compounds that may be used to form quaternary ammonium salts. In addition, o-chlorobenzyl bromide, phenethyl chloride and propargyl bromide may be used to form salts.

The compounds of this invention have useful medicinal properties and are indicated to be psychotherapeutic agents. These compounds have a tranquilizing efiect in animals; they thus have veterinary applications. They also form salts with acidic antibiotics and thus can be used to isolate and purify such antibiotics, particularly penicillin, from fermentation broths or solutions containing the same.

The following examples are presented to show specific methods of producing certain of the novel compounds included within this invention. It is understood, however, that these examples are included only for the purposes of illustration, and that the invention is not to be restricted to the embodiments specifically disclosed therein.

EXAMPLE 1 N -me thyl-Z- benzhydry [aminomethyl) -pyrrolidine A mixture containing 40.0 g. (0.30 mole) of N-methyl- 3-chloropiperidine, 54.9 g. (0.30 mole) of benzhydrylamine and 300 cc. of di-isobutyl'carbinal was stirred and refluxed for 15 hours. The precipitate was removed by filtration and the filtrate concentrated by distillation in vacuo. The residual oil and the precipitate were placed in 250 cc. of water, the aqueous mixture made strongly alkaline with potassium hydroxide and extracted with ether. The ether extracts were dried with potassium carbonate and the product collected by distillation; B. P. 200-235 C. (0.50 mm).

.with ether.

EXAMPLE 2 N-methyl-Z-(benzhydrylaminomethyl) -pyrrolidine I 1 CH 47.8 g. (0.l7 mole) of base (Example 1) were converted to the hydrochloride in ether by the addition of ethereal hydrochloric acid. The precipitate was isolated by filtration and recrystallized from a mixture of 200 cc. ethanol and 300 cc. isopropyl alcohol; M. P. 246247 C.

EXAMPLE. 3

l N-ntethylfz-(p-chlorobenzhydrwlaminomethyl) pyrrolidine CH: p

fluxed with stirring for 16 hours.

removed by distillation in vacuo, the residue suspended in 700 cc. of Water, the aqueous mixture made strongly alkaline. with solid potassium hydroxide and extracted n The ether extracts Were-dried with potassium carbonate and the product collected by distillation; BrP.

-170173 C. (0.04 mm.).

EXAMPLE, 4

N -m'ethyl-2- p-chlorobenzhydrylaminomethyl pyrrolidine dihydrochloride OHr-NHC 1 .2H01 Mi -C1) CH3 The dihydrochloride of the base (Example 3) was formed in ether by the addition of ethereal hydrochloric acid to I OH:

Thecrude product was recrystallized A mixture of 28.0 g. (0.10 mole) of N-methyl-Z-(benzhydrylaminomethyl)-pyrrolidine (Example 1), 29.0 g. (0.56 mole) of 88% formic acid, 10.0 g. (0.12 mole) of formaldehyde was refluxed for five hours.

To the reaction mixture was then added l2 cc. of concentrated hydrochloric acid and the solvents removed by distillation in vacuo. The residue was partially dissolved in hot acetone and the unreacted N-methyl-Z-(benzhydrylaminomethyllpyrrolidine dihydrochloride removed by fi tion. The filtrate was evaporated to dryness, the res dissolved in water, the aqueous solution made stro alkaline by the addition of solid potassium hydro and the alkaline mixture extracted with ether. The e extracts were dried with potassium carbonate and product collected by v distillation; B. P. l33-135 (0.04 mm.).

EXAMPLE 6 "l .-2Ho1 a CH: To an isopropylralcohqlic solution of the-base (Exar 5) was added ethereal hydrochloric acid untilthe s tion was strongly acid. The crystalhne' product me at 225-226 C.

.Various changesand modifications of the inven can be made and, to the extent that such variations corporate the spirit ofthis inv ention, they are inter to'be included within the scope; of the appended clair What is claimed is:

1. A member of the group of compounds of the forn and ' i N QHi-N-L-CQ wherein R represents a lower alkyl group, R represt a. member of the group consisting of hydrogen and 10 alkyl groups, Z is a lower alkylene group, and X an are rnembers of the group consisting of phenyl, ni phenyl, lower alkyl-phenyl, lower alkoxy-phenyl halophenyl groups, and nontoxic lower alkyl quatern ammonium salts, nontoxic phenyl-lower alkyl quatern ammonium salts and nontoxic acid addition salts then 2. N-methyl-2-(benzhydrylarninomethyl)-pyrrolidin 3. N methyl 2 (p chlorobenzhydrylaminometh pyrrolidine.

4. N N methyl 2 pyrrolidylrnethyl) N metl benzhydrylamine.

5. N ethyl 2 (3,3 diphenylpropylaminomethyj pyrrolidine.

6. N propyl 2 (4,4 diphenylbutylaminomethyi pyrrolidine.

7.1 N methyl 2 (p-methylbenzhydrylaminometh pyrrolidine.

" References Cited in the file of this patent Reitsema: LAm. Chem. Soc., ,vol. 71, pp. 204' (1949 

1. A MEMBER OF THE GROUP OF COMPOUNDS OF THE FORMULA
 2. N-MERTHYL-2 (BENZHYDRYLAMINOMETHYL)-PYRROLIDINE. 